Substance P and eledoisin are naturally occurring undecapeptides belonging to the tachykinin family of peptides so named because of their prompt stimulatory action on smooth muscle. Eledoisin was originally isolated from the posterior salivary glands of the Mediterranean octopod Eledone moschata. A mammalian tachykinin is substance P, a neuropeptide originally isolated from gut. These peptides have the following amino acid sequences: ##STR2##
These materials suffer the typical shortcomings of pharmacologically active peptides such as susceptibility to enzymatic degradation and lack of pharmacological specificity which severely limit their use as therapeutic agents. Modification by incorporation of D-amino acids and/or N-methyl amino acids and shortening of the peptides to six amino acids has produced compounds with enhanced metabolic stability (Sandberg et al., J. Med. Chem., 25, 1009 (1982); The Peptides, Vol. II, Schroder and Lubke, Eds., pp. 137-152 (1966)).
The shortest active sequence demonstrating eledoisin activity and selectivity has been ##STR3## which corresponds to the last six amino acids of substance P.
Another technique which has been employed for altering the pharmacological and biochemical properties of peptides comprises the introduction of conformational constraints imposed by formation of relatively rigid ring systems within the peptide chains (Freidinger et al., Science, 210, 656-658 (1980); Freidinger et al., J. Org. Chem., 47, 104 (1982)).
Now, with this invention there are provided peptides related to substance P and eledoisin with increased activity, increased selectivity for eledoisin receptors and increased resistance to protease degradation through the use of lactam conformational constraints, optionally in combination with other methods of peptide modification.
In the specification and claims hereof the following abbreviations are employed:
______________________________________ &lt;Glu Pyroglutamic acid ##STR4## Pro Proline ##STR5## Ser Serine ##STR6## Lys Lysine ##STR7## Asp Aspartic acid ##STR8## Ala Alanine ##STR9## Phe Phenylalanine ##STR10## NMePhe Nmethyl phenylalanine ##STR11## Ile Isoleucine ##STR12## Gly Glycine H.sub.2 NCH.sub.2COOH Leu Leucine ##STR13## Met Methionine ##STR14## Arg Arginine ##STR15## Gln Glutamine ##STR16## AcAla Acetylalanine ##STR17## AcPhe Acetylphenyl- alanine ##STR18## Tyr Tyrosine ##STR19## Val Valine ##STR20## ______________________________________